Tumor-specific CD4 T cells instruct monocyte fate in pancreatic ductal adenocarcinoma
Michael T. Patterson,
Adam L. Burrack,
Yingzheng Xu,
Grant H. Hickok,
Zoe C. Schmiechen,
Samuel Becker,
Eduardo Cruz-Hinojoza,
Patricia R. Schrank,
Ainsley E. Kennedy,
Maria M. Firulyova,
Ebony A. Miller,
Konstantin Zaitsev,
Jesse W. Williams,
Ingunn M. Stromnes
Affiliations
Michael T. Patterson
Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, USA
Adam L. Burrack
Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA
Yingzheng Xu
Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, USA
Grant H. Hickok
Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA
Zoe C. Schmiechen
Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA
Samuel Becker
Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA
Eduardo Cruz-Hinojoza
Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA
Patricia R. Schrank
Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, USA
Ainsley E. Kennedy
Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, USA
Maria M. Firulyova
Computer Technologies Laboratory, ITMO University, Saint-Petersburg, Russia; National Medical Research Center, Saint-Petersburg, Russia
Ebony A. Miller
Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA
Konstantin Zaitsev
Computer Technologies Laboratory, ITMO University, Saint-Petersburg, Russia
Jesse W. Williams
Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, USA; Corresponding author
Ingunn M. Stromnes
Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Masonic Cancer Center and University of Minnesota Medical School, Minneapolis, MN 55414, USA; Center for Genome Engineering, University of Minnesota Medical School, Minneapolis, MN 55414, USA; Corresponding author
Summary: Pancreatic ductal adenocarcinoma (PDA) orchestrates a suppressive tumor microenvironment that fosters immunotherapy resistance. Tumor-associated macrophages (TAMs) are the principal immune cell infiltrating PDA and are heterogeneous. Here, by employing macrophage fate-mapping approaches and single-cell RNA sequencing, we show that monocytes give rise to most macrophage subsets in PDA. Tumor-specific CD4, but not CD8, T cells promote monocyte differentiation into MHCIIhi anti-tumor macrophages. By conditional major histocompatibility complex (MHC) class II deletion on monocyte-derived macrophages, we show that tumor antigen presentation is required for instructing monocyte differentiation into anti-tumor macrophages, promoting Th1 cells, abrogating Treg cells, and mitigating CD8 T cell exhaustion. Non-redundant IFNγ and CD40 promote MHCIIhi anti-tumor macrophages. Intratumoral monocytes adopt a pro-tumor fate indistinguishable from that of tissue-resident macrophages following loss of macrophage MHC class II or tumor-specific CD4 T cells. Thus, tumor antigen presentation by macrophages to CD4 T cells dictates TAM fate and is a major determinant of macrophage heterogeneity in cancer.
